Hypoglycaemia has long been recognised as a dangerous side-effect of treatment of diabetes with insulin or insulin secretagogues. With its potential to disrupt cerebral function, hypoglycaemia can have a major effect on peoples' lives. Study findings have suggested that hypoglycaemia is associated with an increased risk of cardiovascular events and mortality. Different mechanisms by which hypoglycaemia might provoke cardiovascular events have been identified in experimental studies, and in clinical studies cardiac arrhythmias have been reported to be induced by hypoglycaemia, with one report describing sudden death during a severe episode. Emerging evidence suggests that the association between hypoglycaemia and cardiovascular events and mortality is likely to be multifactorial. The association is probably partly caused by confounding, with hypoglycaemia occurring more frequently in people with comorbidities who are also more likely to die than those without. However, people with type 1 or type 2 diabetes also seem at risk of hypoglycaemia-induced cardiovascular effects. This risk should be recognised by clinicians when agreeing glycaemic goals with patients and choosing appropriate glucose-lowering therapies.

Hypoglycemia is the most common complication of diabetes, causing morbidity and death. Recurrent hypoglycemia alters the cascade of physiological and behavioral responses that maintain euglycemia. The extent to which these responses are normally triggered by decreased whole-brain cerebral glucose metabolism (CMRglc) has not been resolved by previous studies. We measured plasma counterregulatory hormonal responses and whole-brain CMRglc (along with blood-to-brain glucose transport rates and brain glucose concentrations) with 1-[11C]-d-glucose positron emission tomography during hyperinsulinemic glucose clamps at nominal plasma glucose concentrations of 90, 75, 60, and 45 mg/dL (5.0, 4.2, 3.3, and 2.5 mmol/L) in 18 healthy young adults. Clear evidence of hypoglycemic physiological counterregulation was first demonstrated between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L) with increases in both plasma epinephrine (P = 0.01) and glucagon (P = 0.01). In contrast, there was no statistically significant change in CMRglc (P = 1.0) between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L), whereas CMRglc significantly decreased (P = 0.02) between 60 mg/dL (3.3 mmol/L) and 45 mg/dL (2.5 mmol/L). Therefore, the increased epinephrine and glucagon secretion with declining plasma glucose concentrations is not in response to a decrease in whole-brain CMRglc.

The view that a hemoglobin A(1c) (A1C) level <7% (55 mmol/mol) is the accepted glycemic goal for most people with diabetes sometimes conflicts with the view that glycemic goals should be individualized and, thus, that somewhat higher A1C levels are appropriate for some, particularly many at risk for iatrogenic hypoglycemia because of treatment with insulin, a sulfonylurea, or a glinide. The relationship between A1C and chronic complications of diabetes is curvilinear, A1C is a relatively weak predictor of cardiovascular disease, and minor elevations of A1C above 7% have not been found to be associated with increased mortality. Iatrogenic hypoglycemia causes recurrent morbidity in diabetes and is sometimes fatal. In those at risk for hypoglycemia, a reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual's diabetes. A somewhat higher A1C level is appropriate in those who have previously experienced hypoglycemia or have potential high risk for hypoglycemia, have a long duration of diabetes, and have a short life expectancy, among other traits. Given the importance of severe hypoglycemia in selecting glycemic goals, it is proposed to expand the classification of severe hypoglycemia beyond a hypoglycemic event requiring assistance from another person to include a measured glucose concentration <50 mg/dL (2.8 mmol/L), a level associated with sudden death.

Hypoglycemia, caused by treatment with a sulfonylurea, a glinide, or insulin coupled with compromised defenses against the resulting falling plasma glucose concentrations, is the limiting factor in the glycemic management of diabetes. It causes recurrent morbidity in most people with type 1 diabetes mellitus (T1DM) and many with advanced type 2 diabetes mellitus (T2DM) and is sometimes fatal; it limits maintenance of euglycemia over a lifetime of diabetes; and it impairs physiological and behavioral defenses against subsequent hypoglycemia. In addition to drug selection and application of diabetes treatment technologies, minimizing hypoglycemia in diabetes includes acknowledging the problem, considering each of the risk factors and applying the principles of intensive glycemic therapy. For most people with diabetes who are at risk for, or suffering from, iatrogenic hypoglycemia these principles include selecting appropriate individualized glycemic goals and providing structured patient education that will often reduce the incidence of hypoglycemia. That is typically coupled with short-term scrupulous avoidance of hypoglycemia that will often reverse impaired awareness of hypoglycemia. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

Hypoglycemia caused by treatment with a sulfonylurea, a glinide, or insulin coupled with compromised defenses against the resulting falling plasma glucose concentrations is a problem for many people with diabetes. It is often recurrent, causes significant morbidity and occasional mortality, limits maintenance of euglycemia, and impairs physiological and behavioral defenses against subsequent hypoglycemia. Minimizing hypoglycemia includes acknowledging the problem; considering each risk factor; and applying the principles of intensive glycemic therapy, including drug selection and selective application of diabetes treatment technologies. For diabetes health-care providers treating most people with diabetes who are at risk for or are suffering from iatrogenic hypoglycemia, these principles include selecting appropriate individualized glycemic goals and providing structured patient education to reduce the incidence of hypoglycemia. This is typically combined with short-term scrupulous avoidance of hypoglycemia, which often will reverse impaired awareness of hypoglycemia. Clearly, the risk of hypoglycemia is modifiable.

The selection of a glycemic goal in a person with diabetes is a compromise between the documented upside of glycemic control—the partial prevention or delay of microvascular complications—and the documented downside of glycemic control—the recurrent morbidity and potential mortality of iatrogenic hypoglycemia. The latter is not an issue if glycemic control is accomplished with drugs that do not cause hypoglycemia or with substantial weight loss. However, hypoglycemia becomes an issue if glycemic control is accomplished with a sulfonylurea, a glinide, or insulin, particularly in the setting of absolute endogenous insulin deficiency with loss of the normal decrease in circulating insulin and increase in glucagon secretion and attenuation of the sympathoadrenal response as plasma glucose concentrations fall. Then the selection of a glycemic goal should be linked to the risk of hypoglycemia. A reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual’s diabetes.

I am pleased that Kerner and Volzke (1) believe, based on their experience and assumptions, that the death rate from hypoglycemia in their patients with type 1 diabetes is lower than in the published literature. In my commentary (2) on the report of McCoy et al. (3) of a 3.4-fold higher mortality in patients with diabetes who self-reported severe hypoglycemia …

OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

Glycemic control is limited by the barrier of hypoglycemia. Recurrent hypoglycemia impairs counterregulatory (CR) hormone responses to subsequent hypoglycemia.

Pancreatic islet alpha-cell glucagon secretion is critically dependent on pancreatic islet beta-cell insulin secretion. Normally, a decrease in the plasma glucose concentration causes a decrease in beta-cell insulin secretion that signals an increase in alpha-cell glucagon secretion during hypoglycemia. In contrast, an increase in the plasma glucose concentration, among other stimuli, causes an increase in beta-cell insulin secretion that signals a decrease, or at least no change, in alpha-cell glucagon secretion after a meal. In absolute endogenous insulin deficiency (i.e. in type 1 diabetes and in advanced type 2 diabetes), however, beta-cell failure results in no decrease in beta-cell insulin secretion and thus no increase in alpha-cell glucagon secretion during hypoglycemia and no increase in beta-cell insulin secretion and thus an increase in alpha-cell glucagon secretion after a meal. In type 1 diabetes and advanced type 2 diabetes, the absence of an increment in glucagon secretion, in the setting of an absent decrement in insulin secretion and an attenuated increment in sympathoadrenal activity, in response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia. In addition, there is increasing evidence that, in the aggregate, suggests that relative hyperglucagonemia, in the setting of deficient insulin secretion, plays a role in the pathogenesis of hyperglycemia in diabetes. If so, abnormal glucagon secretion is involved in the pathogenesis of both hypoglycemia and hyperglycemia in diabetes. (Endocrinology 153: 1039-1048, 2012)

OBJECTIVE The central nervous system mechanisms of defenses against falling plasma glucose concentrations, and how they go awry and result in iatrogenic hypoglycemia in diabetes, are not known. Hypoglycemic plasma glucose concentrations of 55 mg/dL (3.0 mmol/L) cause symptoms, activate glucose counterregulatory systems, and increase synaptic activity in a network of brain regions including the dorsal midline thalamus in humans. We tested the hypothesis that slightly subphysiological plasma glucose concentrations of 65 mg/dL (3.6 mmol/L), which do not cause symptoms but do activate glucose counterregulatory systems, also activate brain synaptic activities. RESEARCH DESIGN AND METHODS We measured relative regional cerebral blood flow (rCBF), an index of synaptic activity, in predefined brain regions with [15O]water positron emission tomography, symptoms, and plasma epinephrine and glucagon concentrations during a 2-h euglycemic (90 mg/dL) to hypoglycemic (55 mg/dL) clamp (n = 20) or a 2-h euglycemic to slight subphysiological (65 mg/dL) clamp (n = 9) in healthy humans. RESULTS Clamped plasma glucose concentrations of 65 mg/dL did not cause hypoglycemic symptoms, but raised plasma epinephrine and glucagon concentrations and increased rCBF (P = 0.007) only in the dorsal midline thalamus. CONCLUSIONS Slightly subphysiological plasma glucose concentrations increase synaptic activity in the dorsal midline thalamus in humans.

SEE RELATED ARTICLE p. 1028 SEE RELATED ARTICLE p. 1028 Despite its documented microvascular1The Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (23169) Google Scholar, 2UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (19346) Google Scholar, 3UK Prospective Diabetes Study (UKPDS) GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7654) Google Scholar and potential macrovascular4The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research GroupIntensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med. 2005; 353: 2643-2653Crossref PubMed Scopus (4253) Google Scholar, 5Holman R.R. 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Neil H.A. 10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589Crossref PubMed Scopus (5471) Google Scholar benefits in both type 1 and type 2 diabetes mellitus, intensive glycemic therapy was not found to produce macrovascular benefits, let alone survival benefits, in 3 recent randomized clinical trials: Action to Control Cardiovascular Risk in Diabetes (ACCORD),6The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6683) Google Scholar Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE),7The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (6180) Google Scholar and Veterans Affairs Diabetes Trial (VADT).8Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (4011) Google Scholar Similarly, it was not found to produce a survival benefit in hyperglycemic intensive care unit patients.9The NICE-SUGAR Study InvestigatorsIntensive versus conventional glucose control in critically ill patients.N Engl J Med. 2009; 360: 1283-1297Crossref PubMed Scopus (3874) Google Scholar, 10Kavanagh B.P. McCowen K.C. Glycemic control in the ICU.N Engl J Med. 2010; 363: 2540-2546Crossref PubMed Scopus (155) Google Scholar, 11Kansagara D. Fu R. Freeman M. Wolf F. Helfand M. Intensive insulin therapy in hospitalized patients: a systematic review.Ann Intern Med. 2011; 154: 268-282Crossref PubMed Scopus (192) Google Scholar Indeed, intensive glycemic therapy resulted in increased mortality in one large trial involving patients with type 2 diabetes6The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6683) Google Scholar and in another large trial involving critically ill individuals (Normoglycemia in Intensive Care—Survival Using Glucose Algorithm Regulation [NICE-SUGAR]).9The NICE-SUGAR Study InvestigatorsIntensive versus conventional glucose control in critically ill patients.N Engl J Med. 2009; 360: 1283-1297Crossref PubMed Scopus (3874) Google Scholar Regardless of the specific causative mechanisms, the latter findings are of concern. It appears that some aspect of intensive therapy increased the risk of death. There is clear evidence that administration of insulin or of an insulin secretagogue can cause fatal hypoglycemia12Bliss M. The Discovery of Insulin. University of Chicago Press, Chicago, IL1984Google Scholar, 13Auer R.N. Progress review: hypoglycemic brain damage.Stroke. 1986; 17: 699-708Crossref PubMed Scopus (197) Google Scholar, 14Clarke D.D. Sokoloff L. Circulation and energy metabolism of the brain.in: Siegel G. Agranoff B. Albers R.T. Molinoff P. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 5th ed. Raven Press, New York, NY1994: 645-680Google Scholar, 15Suh S.W. Aoyama K. Chen Y. et al.Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia.J Neurosci. 2003; 23: 10681-10690PubMed Google Scholar and can do so in patients with diabetes.16Deckert T. Poulsen J.E. Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one I. Survival, causes of death, and complications.Diabetologia. 1978; 14: 363-370Crossref PubMed Scopus (383) Google Scholar, 17Tunbridge W.M.G. Factors contributing to deaths of diabetics under fifty years of age.Lancet. 1981; 2: 569-572Abstract PubMed Scopus (141) Google Scholar, 18Laing S.P. Swerdlow A.J. Slater S.D. et al.The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus.Diabet Med. 1999; 16: 459-465Crossref PubMed Scopus (153) Google Scholar, 19The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research GroupLong-term effect of diabetes and its treatment on cognitive function.N Engl J Med. 2007; 356: 1842-1852Crossref PubMed Scopus (548) Google Scholar, 20Feltbower R.G. Bodansky H.J. Patterson C.C. et al.Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes.Diabetes Care. 2008; 31: 922-926Crossref PubMed Scopus (142) Google Scholar, 21Skrivarhaug T. Bangstad H.-J. Stene L.C. Sandvik L. Hanssen K.F. Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway.Diabetologia. 2006; 49: 298-305Crossref PubMed Scopus (300) Google Scholar, 22Tanenberg R.J. Newton C.A. Drake III, A.J. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system.Endocr Pract. 2010; 16: 244-248Crossref PubMed Scopus (177) Google Scholar, 23Goldman D. The electrocardiogram in insulin shock.Arch Intern Med. 1940; 66: 93-108Crossref Scopus (13) Google Scholar, 24Chelliah Y.R. Ventricular arrhythmias associated with hypoglycaemia.Anaesth Intensive Care. 2000; 28: 698-700Crossref PubMed Google Scholar, 25Ferner R.E. Neil H.A. Sulphonylureas and hypoglycaemia.BMJ. 1988; 296: 949-950Crossref PubMed Scopus (147) Google Scholar, 26Gerich J.E. Oral hypoglycemic agents.N Engl J Med. 1989; 321: 1231-1245Crossref PubMed Scopus (470) Google Scholar, 27Holstein A. Egberts E.H. Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes.Exp Clin Endocrinol Diabetes. 2003; 111: 405-414Crossref PubMed Scopus (116) Google Scholar, 28Johnston S.S. Conner C. Aagren M. Smith D.M. Bouchard J. Brett J. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes.Diabetes Care. 2011; 34: 1164-1170Crossref PubMed Scopus (155) Google Scholar, 29Schramm T.K. Gislason G.H. Vaag A. et al.Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study.Eur Heart J. 2011; 32: 1900-1908Crossref PubMed Scopus (364) Google Scholar, 30Currie C.J. Peters J.R. Tynan A. et al.Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar, 31Colayco D.C. Niu F. McCombs J.S. Cheetham T.C. A1C and cardiovascular outcomes in type 2 diabetes.Diabetes Care. 2011; 34: 77-83Crossref PubMed Scopus (83) Google Scholar, 32Huang E.S. Liu J.Y. Moffet H.H. John P.M. Karter A.J. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.Diabetes Care. 2011; 34: 1329-1336Crossref PubMed Scopus (267) Google Scholar First, the Toronto investigators' insulin extract sometimes killed diabetic dogs, and they found that convulsions following insulin extract administration were associated with low blood glucose concentrations and could be prevented by intravenous glucose administration in rabbits as early as 1922.12Bliss M. The Discovery of Insulin. University of Chicago Press, Chicago, IL1984Google Scholar Second, high mortality rates characterize experimental hypoglycemia.13Auer R.N. Progress review: hypoglycemic brain damage.Stroke. 1986; 17: 699-708Crossref PubMed Scopus (197) Google Scholar, 14Clarke D.D. Sokoloff L. Circulation and energy metabolism of the brain.in: Siegel G. Agranoff B. Albers R.T. Molinoff P. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 5th ed. Raven Press, New York, NY1994: 645-680Google Scholar, 15Suh S.W. Aoyama K. Chen Y. et al.Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia.J Neurosci. 2003; 23: 10681-10690PubMed Google Scholar Thus, there is no doubt that hypoglycemia can kill. Third, there is a reported iatrogenic mortality rate in type 1 diabetes.16Deckert T. Poulsen J.E. Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one I. Survival, causes of death, and complications.Diabetologia. 1978; 14: 363-370Crossref PubMed Scopus (383) Google Scholar, 17Tunbridge W.M.G. Factors contributing to deaths of diabetics under fifty years of age.Lancet. 1981; 2: 569-572Abstract PubMed Scopus (141) Google Scholar, 18Laing S.P. Swerdlow A.J. Slater S.D. et al.The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus.Diabet Med. 1999; 16: 459-465Crossref PubMed Scopus (153) Google Scholar, 19The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research GroupLong-term effect of diabetes and its treatment on cognitive function.N Engl J Med. 2007; 356: 1842-1852Crossref PubMed Scopus (548) Google Scholar, 20Feltbower R.G. Bodansky H.J. Patterson C.C. et al.Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes.Diabetes Care. 2008; 31: 922-926Crossref PubMed Scopus (142) Google Scholar, 21Skrivarhaug T. Bangstad H.-J. Stene L.C. Sandvik L. Hanssen K.F. Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway.Diabetologia. 2006; 49: 298-305Crossref PubMed Scopus (300) Google Scholar Older estimates were that 2%-4% of patients with type 1 diabetes die from hypoglycemia.16Deckert T. Poulsen J.E. Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one I. Survival, causes of death, and complications.Diabetologia. 1978; 14: 363-370Crossref PubMed Scopus (383) Google Scholar, 17Tunbridge W.M.G. Factors contributing to deaths of diabetics under fifty years of age.Lancet. 1981; 2: 569-572Abstract PubMed Scopus (141) Google Scholar, 18Laing S.P. Swerdlow A.J. Slater S.D. et al.The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus.Diabet Med. 1999; 16: 459-465Crossref PubMed Scopus (153) Google Scholar More recent estimates are that 6%,19The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research GroupLong-term effect of diabetes and its treatment on cognitive function.N Engl J Med. 2007; 356: 1842-1852Crossref PubMed Scopus (548) Google Scholar 7%,20Feltbower R.G. Bodansky H.J. Patterson C.C. et al.Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes.Diabetes Care. 2008; 31: 922-926Crossref PubMed Scopus (142) Google Scholar or 10%21Skrivarhaug T. Bangstad H.-J. Stene L.C. Sandvik L. Hanssen K.F. Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway.Diabetologia. 2006; 49: 298-305Crossref PubMed Scopus (300) Google Scholar of those with type 1 diabetes die from hypoglycemia. Fourth, continuous glucose monitoring subcutaneous glucose concentrations that fell to <10 mg/dL (0.6 mmol/L) were associated temporally with the death of a patient with type 1 diabetes.22Tanenberg R.J. Newton C.A. Drake III, A.J. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system.Endocr Pract. 2010; 16: 244-248Crossref PubMed Scopus (177) Google Scholar Fifth, an association between therapeutic insulin-induced hypoglycemia and cardiac arrhythmias has long been recognized,23Goldman D. The electrocardiogram in insulin shock.Arch Intern Med. 1940; 66: 93-108Crossref Scopus (13) Google Scholar and a patient with hypoglycemia who developed ventricular tachycardia that reverted to sinus rhythm after intravenous glucose administration has been reported.24Chelliah Y.R. Ventricular arrhythmias associated with hypoglycaemia.Anaesth Intensive Care. 2000; 28: 698-700Crossref PubMed Google Scholar Sixth, hypoglycemic deaths have been reported in many patients with type 2 diabetes.25Ferner R.E. Neil H.A. Sulphonylureas and hypoglycaemia.BMJ. 1988; 296: 949-950Crossref PubMed Scopus (147) Google Scholar, 26Gerich J.E. Oral hypoglycemic agents.N Engl J Med. 1989; 321: 1231-1245Crossref PubMed Scopus (470) Google Scholar, 27Holstein A. Egberts E.H. Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes.Exp Clin Endocrinol Diabetes. 2003; 111: 405-414Crossref PubMed Scopus (116) Google Scholar Indeed, an association between hypoglycemic events and acute cardiovascular events in type 2 diabetes has been noted28Johnston S.S. Conner C. Aagren M. Smith D.M. Bouchard J. Brett J. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes.Diabetes Care. 2011; 34: 1164-1170Crossref PubMed Scopus (155) Google Scholar; a Danish survey disclosed increased cardiovascular and all-cause mortality in patients treated with sulfonylureas compared with those treated with metformin29Schramm T.K. Gislason G.H. Vaag A. et al.Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study.Eur Heart J. 2011; 32: 1900-1908Crossref PubMed Scopus (364) Google Scholar; and an association between low hemoglobin A1c (A1C) levels and mortality in patients with type 2 diabetes has been reported.30Currie C.J. Peters J.R. Tynan A. et al.Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar, 31Colayco D.C. Niu F. McCombs J.S. Cheetham T.C. A1C and cardiovascular outcomes in type 2 diabetes.Diabetes Care. 2011; 34: 77-83Crossref PubMed Scopus (83) Google Scholar, 32Huang E.S. Liu J.Y. Moffet H.H. John P.M. Karter A.J. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.Diabetes Care. 2011; 34: 1329-1336Crossref PubMed Scopus (267) Google Scholar With all of this evidence, it is simply not credible to contend, or even imply, that iatrogenic hypoglycemia is never fatal. Given the association between hypoglycemia and mortality in ACCORD,6The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6683) Google Scholar NICE-SUGAR,9The NICE-SUGAR Study InvestigatorsIntensive versus conventional glucose control in critically ill patients.N Engl J Med. 2009; 360: 1283-1297Crossref PubMed Scopus (3874) Google Scholar and other trials,7The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (6180) Google Scholar, 8Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (4011) Google Scholar and the fact that hypoglycemia can be fatal, as just summarized,12Bliss M. The Discovery of Insulin. University of Chicago Press, Chicago, IL1984Google Scholar, 13Auer R.N. Progress review: hypoglycemic brain damage.Stroke. 1986; 17: 699-708Crossref PubMed Scopus (197) Google Scholar, 14Clarke D.D. Sokoloff L. Circulation and energy metabolism of the brain.in: Siegel G. Agranoff B. Albers R.T. Molinoff P. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 5th ed. Raven Press, New York, NY1994: 645-680Google Scholar, 15Suh S.W. Aoyama K. Chen Y. et al.Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia.J Neurosci. 2003; 23: 10681-10690PubMed Google Scholar, 16Deckert T. Poulsen J.E. Larsen M. Prognosis of diabetics with diabetes onset before the age of thirty-one I. Survival, causes of death, and complications.Diabetologia. 1978; 14: 363-370Crossref PubMed Scopus (383) Google Scholar, 17Tunbridge W.M.G. Factors contributing to deaths of diabetics under fifty years of age.Lancet. 1981; 2: 569-572Abstract PubMed Scopus (141) Google Scholar, 18Laing S.P. Swerdlow A.J. Slater S.D. et al.The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus.Diabet Med. 1999; 16: 459-465Crossref PubMed Scopus (153) Google Scholar, 19The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research GroupLong-term effect of diabetes and its treatment on cognitive function.N Engl J Med. 2007; 356: 1842-1852Crossref PubMed Scopus (548) Google Scholar, 20Feltbower R.G. Bodansky H.J. Patterson C.C. et al.Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes.Diabetes Care. 2008; 31: 922-926Crossref PubMed Scopus (142) Google Scholar, 21Skrivarhaug T. Bangstad H.-J. Stene L.C. Sandvik L. Hanssen K.F. Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway.Diabetologia. 2006; 49: 298-305Crossref PubMed Scopus (300) Google Scholar, 22Tanenberg R.J. Newton C.A. Drake III, A.J. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system.Endocr Pract. 2010; 16: 244-248Crossref PubMed Scopus (177) Google Scholar, 23Goldman D. The electrocardiogram in insulin shock.Arch Intern Med. 1940; 66: 93-108Crossref Scopus (13) Google Scholar, 24Chelliah Y.R. Ventricular arrhythmias associated with hypoglycaemia.Anaesth Intensive Care. 2000; 28: 698-700Crossref PubMed Google Scholar, 25Ferner R.E. Neil H.A. Sulphonylureas and hypoglycaemia.BMJ. 1988; 296: 949-950Crossref PubMed Scopus (147) Google Scholar, 26Gerich J.E. Oral hypoglycemic agents.N Engl J Med. 1989; 321: 1231-1245Crossref PubMed Scopus (470) Google Scholar, 27Holstein A. Egberts E.H. Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes.Exp Clin Endocrinol Diabetes. 2003; 111: 405-414Crossref PubMed Scopus (116) Google Scholar, 28Johnston S.S. Conner C. Aagren M. Smith D.M. Bouchard J. Brett J. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes.Diabetes Care. 2011; 34: 1164-1170Crossref PubMed Scopus (155) Google Scholar, 29Schramm T.K. Gislason G.H. Vaag A. et al.Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study.Eur Heart J. 2011; 32: 1900-1908Crossref PubMed Scopus (364) Google Scholar, 30Currie C.J. Peters J.R. Tynan A. et al.Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar, 31Colayco D.C. Niu F. McCombs J.S. Cheetham T.C. A1C and cardiovascular outcomes in type 2 diabetes.Diabetes Care. 2011; 34: 77-83Crossref PubMed Scopus (83) Google Scholar, 32Huang E.S. Liu J.Y. Moffet H.H. John P.M. Karter A.J. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.Diabetes Care. 2011; 34: 1329-1336Crossref PubMed Scopus (267) Google Scholar it is reasonable to suspect that iatrogenic hypoglycemia was a cause of excess mortality during intensive glycemic therapy in ACCORD6The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6683) Google Scholar and in NICE-SUGAR.9The NICE-SUGAR Study InvestigatorsIntensive versus conventional glucose control in critically ill patients.N Engl J Med. 2009; 360: 1283-1297Crossref PubMed Scopus (3874) Google Scholar Excessive mortality during intensive glycemic therapy of type 2 diabetes in ACCORD could have been the result of chance, a nonglycemic effect of some aspect of the intensive therapy regimen (eg, weight gain, a side effect of one of the several drugs used or something else), or hypoglycemia.33Riddle M.C. Ambrosius W.T. Brillon D.J. et al.Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial.Diabetes Care. 2010; 33: 983-990Crossref PubMed Scopus (367) Google Scholar, 34Lachin J.M. Point: intensive glycemic control and mortality in ACCORD—a chance finding?.Diabetes Care. 2010; 33: 2719-2721Crossref PubMed Scopus (17) Google Scholar, 35Riddle M.C. Counterpoint: intensive glucose control and mortality in ACCORD—still looking for clues.Diabetes Care. 2010; 33: 2722-2724Crossref PubMed Scopus (31) Google Scholar The plasma glucose concentrations at the times of death are not known. Therefore, conclusions to the contrary36Miller M.E. Bonds D.E. Gerstein H.C. et al.The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study.BMJ. 2010; 340: b5444Crossref PubMed Scopus (358) Google Scholar, 37Bonds D.E. Miller M.E. Bergenstal R.M. et al.The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.BMJ. 2010; 340: b4909Crossref PubMed Scopus (784) Google Scholar, 38The ACCORD Study GroupLong-term effects of intensive glucose lowering on cardiovascular outcomes.N Engl J Med. 2011; 364: 818-828Crossref PubMed Scopus (857) Google Scholar notwithstanding, it is not possible to conclude with certainty whether hypoglycemia was or was not a culprit. Interestingly, mortality in the intensive therapy group was directly related to the A1C level.33Riddle M.C. Ambrosius W.T. Brillon D.J. et al.Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial.Diabetes Care. 2010; 33: 983-990Crossref PubMed Scopus (367) Google Scholar However, that does not exclude hypoglycemia as a cause of mortality. In ACCORD there were aggressive goals for the intensive therapy group, including an A1C <6%, and a plan to add drugs or increase doses of drugs monthly if those goals were not being met. Thus, it may be that, rather than attaining an A1C <6%, striving for that A1C and failing to achieve it led to even more aggressive glycemic therapy and excess mortality in ACCORD.39Skyler J.S. Glycemia and cardiovascular diseases in type 2 diabetes.J Intern Med. 2010; 268: 468-470Crossref PubMed Scopus (3) Google Scholar Notably, the fact that there was no significant difference in all-cause mortality or in severe hypoglycemia rates in the 2 groups after the transition to the same, less intensive glycemic goals38The ACCORD Study GroupLong-term effects of intensive glucose lowering on cardiovascular outcomes.N Engl J Med. 2011; 364: 818-828Crossref PubMed Scopus (857) Google Scholar further indicates that there was something about the pretransition intensive glycemic therapy regimen that led to excess mortality. Based on their finding, not only of an association between severe hypoglycemia and cardiovascular death, but also associations between severe hypoglycemia and nonvascular outcomes in type 2 diabetes, Zoungas et al40Zoungas S. Patel A. Chalmers J. et al.Severe hypoglycemia and risks of vascular events and death.N Engl J Med. 2010; 363: 1410-1418Crossref PubMed Scopus (1213) Google Scholar suggested that severe hypoglycemia might be a direct cause of death or it might be a marker of vulnerability to another cause of death. The latter is the tack pursued by Boucai et al41Boucai L. Southern W.N. Zonszein J. Hypoglycemia-associated mortality is not drug-associated but linked to comorbidities.Am J Med. 2011; 124: 1028-1035Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar in this issue of the Journal. However, it is not clear how such a nonvascular cause of death would lead to severe hypoglycemia, the putative marker. One can only speculate that it might have been malnutrition leading to both severe hypoglycemia and death. Furthermore, the lack of a temporal relationship between an episode of recognized severe hypoglycemia and death is not a compelling argument because it is conceivable that hypoglycemic episodes, including one at the time of death, were not recognized. Finally, it does not follow that a patient with a comorbidity—for example, ischemic heart disease—cannot die from hypoglycemia because he or she has that comorbidity. Indeed, for reasons developed later, it is probable that such an individual would be more likely to suffer a fatal event, for example, a ventricular arrhythmia, during a hypoglycemic episode. The finding of excess mortality or cardiovascular events in patients with type 2 diabetes with A1C levels in the lower, as well the higher ranges,30Currie C.J. Peters J.R. Tynan A. et al.Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar, 31Colayco D.C. Niu F. McCombs J.S. Cheetham T.C. A1C and cardiovascular outcomes in type 2 diabetes.Diabetes Care. 2011; 34: 77-83Crossref PubMed Scopus (83) Google Scholar, 32Huang E.S. Liu J.Y. Moffet H.H. John P.M. Karter A.J. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.Diabetes Care. 2011; 34: 1329-1336Crossref PubMed Scopus (267) Google Scholar would seem to imply a direct effect of hypoglycemia. In the UK General Practice Research Database,30Currie C.J. Peters J.R. Tynan A. et al.Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar mortality of patients with type 2 diabetes and A1C levels in the lower deciles was increased in those treated with a sulfonylurea and, to a greater extent, in those treated with insulin, drugs that can cause hypoglycemia. In the Kaiser Permanente Southern California database,31Colayco D.C. Niu F. McCombs J.S. Cheetham T.C. A1C and cardiovascular outcomes in type 2 diabetes.Diabetes Care. 2011; 34: 77-83Crossref PubMed Scopus (83) Google Scholar the risk of a cardiovascular event (nonfatal myocardial infarction or stroke or cardiovascular death) was increased in patients with type 2 diabetes and an A1C ≤6%. The risk was increased in those treated with a sulfonylurea and to a greater extent in those treated with insulin—drugs that can cause hypoglycemia—but not in those treated with metformin. An association between A1C levels <6% and mortality also has been reported in older patients with type 2 diabetes.32Huang E.S. Liu J.Y. Moffet H.H. John P.M. Karter A.J. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study.Diabetes Care. 2011; 34: 1329-1336Crossref PubMed Scopus (267) Google Scholar (A report of increased mortality of initially nondiabetic individuals with low A1C levels42Selvin E. Steffes M.W. Zhu H. et al.Glycated hemoglobin, diabetes and cardiovascular risk in nondiabetic adults.N Engl J Med. 2010; 362: 800-811Crossref PubMed Scopus (1181) Google Scholar was not confirmed.43Pfister R. Sharp S.J. Luben R. Khaw K.T. Wareham N.J. No evidence of an increased mortality risk associated with low levels of glycated haemoglobin in a non-diabetic UK population.Diabetologia. 2011; 54: 2025-2032Crossref PubMed Scopus (31) Google Scholar In the latter data set, the hazard ratio for all-cause mortality in nondiabetic individuals was virtually constant across the low A1C range.) Prolonged, profound hypoglycemia can cause brain death.13Auer R.N. Progress review: hypoglycemic brain damage.Stroke. 1986; 17: 699-708Crossref PubMed Scopus (197) Google Scholar, 14Clarke D.D. Sokoloff L. Circulation and energy metabolism of the brain.in: Siegel G. Agranoff B. Albers R.T. Molinoff P. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 5th ed. Raven Press, New York, NY1994: 645-680Google Scholar, 15Suh S.W. Aoyama K. Chen Y. et al.Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia.J Neurosci. 2003; 23: 10681-10690PubMed Google Scholar, 44Suh S.W. Hamby A.M. Swanson R.A. Hypoglycemia, brain energetics, and hypoglycemic neuronal death.GLIA. 2007; 55: 1280-1286Crossref PubMed Scopus (159) Google Scholar, 45Cryer P.E. Hypoglycemia, functional brain failure, and brain death.J Clin Invest. 2007; 117: 868-870Crossref PubMed Scopus (247) Google Scholar The mechanism is thought to be sustained increased glutamate release and receptor activation when plasma glucose concentrations are <18 mg/dL (1.0 mmol/L), the electroencephalogram is isoelectric, and brain glucose and glycogen levels are unmeasurably low. Fortunately, those conditions occur very rarely in patients with diabetes. Thus, most fatal hypoglycemic episodes are the result of other mechanisms, presumably cardiac arrhythmias.45Cryer P.E. Hypoglycemia, functional brain failure, and brain death.J Clin Invest. 2007; 117: 868-870Crossref PubMed Scopus (247) Google Scholar The mechanisms of fatal hypoglycemia-induced ventricular arrhythmias have been reviewed.46Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence.Diabetologia. 2010; 53: 1552-1561Crossref PubMed Scopus (123) Google Scholar, 47Frier B.M. Schernthaner G. Heller S.R. Hypoglycemia and cardiovascular risks.Diabetes Care. 2011; 34: S132-S137Crossref PubMed Scopus (276) Google Scholar One mechanism is impaired ventricular repolarization, reflected in a prolonged corrected QT (QTc) interval in the electrocardiogram. A prolonged QTc interval is known to be associated with lethal ventricular arrhythmias. Pathogenic factors include, but are not limited to, sympathoadrenal activation and hypokalemia during hypoglycemia. QTc interval prolongation occurs during experimental and clinical hypoglycemia in patients with type 1 diabetes.48Robinson R.T. Harris N.D. Ireland R.H. Macdonald I.A. Heller S.R. Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with type 1 diabetes.Diabetologia. 2004; 47: 312-315Crossref PubMed Scopus (118) Google Scholar, 49Murphy N.P. Ford-Adams M.E. Ong K.K. et al.Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes.Diabetologia. 2004; 47: 1940-1947Crossref PubMed Scopus (72) Google Scholar, 50Gill G.V. Woodward A. Casson I.F. Weston P.J. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the ‘dead in bed’ syndrome revisited.Diabetologia. 2009; 52: 42-45Crossref PubMed Scopus (250) Google Scholar Iatrogenic hypoglycemia in diabetes is the result of the interplay of absolute or relative therapeutic hyperinsulinemia and compromised defenses against the resulting falling plasma glucose concentrations.51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar The compromised defenses include absent decrements in insulin, absent increments in glucagon, and attenuated increments in epinephrine, causing the syndrome of defective glucose counter-regulation and attenuated increments in sympathoadrenal activity, causing the syndrome of hypoglycemia unawareness. Because of the key roles of attenuated adrenomedullary and sympathetic neural responses in these syndromes, defective glucose counter-regulation and hypoglycemia unawareness are conceptualized as components of hypoglycemia-associated autonomic failure (HAAF) in diabetes.51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar HAAF is typically caused by recent antecedent iatrogenic hypoglycemia. It is now recognized that recent antecedent hypoglycemia also reduces baroreflex sensitivity.52Adler G.K. Bonyhay I. Failing H. Waring E. Dotson S. Freeman R. Antecedent hypoglycemia impairs autonomic cardiovascular function: implications for rigorous glycemic control.Diabetes. 2009; 58: 360-366Crossref PubMed Scopus (183) Google Scholar That cardiovascular HAAF is entirely analogous to metabolic HAAF.51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar Thus, the construct of hypoglycemic mortality shown in the Figure is plausible. First, recent antecedent hypoglycemia causes cardiovascular HAAF, including reduced baroreflex sensitivity and the resulting increased vulnerability to a ventricular arrhythmia. Second, recent antecedent hypoglycemia causes metabolic HAAF with an increased risk for an episode of iatrogenic hypoglycemia with sympathoadrenal activation that, through an array of mechanisms including abnormal cardiac repolarization, could trigger a ventricular arrhythmia and sudden death. Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes.51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar It causes recurrent morbidity in most patients with type 1 diabetes and many with advanced type 2 diabetes, and, as summarized here, is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and thus, full realization of the benefits of glycemic control. It impairs defenses against subsequent falling plasma glucose concentrations and therefore causes a vicious cycle of recurrent hypoglycemia. Clearly, there are many compelling reasons to minimize the risk of hypoglycemia in patients with diabetes. Consideration of diabetes trials2UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (19346) Google Scholar, 3UK Prospective Diabetes Study (UKPDS) GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (7654) Google Scholar, 6The Action to Control Cardiovascular Risk in Diabetes Study GroupEffects of intensive glucose lowering in type 2 diabetes.N Engl J Med. 2008; 358: 2545-2559Crossref PubMed Scopus (6683) Google Scholar, 7The ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (6180) Google Scholar, 8Duckworth W. Abraira C. Moritz T. et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med. 2009; 360: 129-139Crossref PubMed Scopus (4011) Google Scholar has prompted some to reconsider glycemic goals for patients with diabetes.53Skyler J.S. Bergenstal R. Bonow R.O. et al.Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials.Diabetes Care. 2009; 32: 187-192Crossref PubMed Scopus (463) Google Scholar, 54Montori V.M. Fernández-Balsells M. Glycemic control in type 2 diabetes: time for an evidence-based about-face?.Ann Intern Med. 2009; 150: 803-808Crossref PubMed Scopus (139) Google Scholar, 55Yudkin J.S. Richter B. Gale E.A.M. Intensified glucose lowering in type 2 diabetes: time for a reappraisal.Diabetologia. 2010; 53: 2079-2085Crossref PubMed Scopus (121) Google Scholar, 56Boussageon R. Bejan-Angoulvant T. Saadatian-Elahi M. et al.Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomized controlled trials.BMJ. 2011; 343: d4169Crossref PubMed Scopus (612) Google Scholar Accepting the premise of individualized glycemic goals, and because the barrier to glycemic control is hypoglycemia,51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar it would seem that the glycemic goal for a given individual at a given point in the progression of his or her diabetes should be based on the drug regimen and the risk of hypoglycemia. A reasonable generic glycemic goal is the lowest A1C that does not cause severe hypoglycemia (that requiring the assistance of another person), preserves awareness of hypoglycemia and causes, at worst, an acceptable number of documented episodes of symptomatic hypoglycemia.57Cryer P.E. Elimination of hypoglycemia from the lives of people affected by Diabetes.Diabetes. 2011; 60: 24-27Crossref PubMed Scopus (25) Google Scholar Absent these conditions, the regimen needs to be adjusted to eliminate the problem51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar or, if serious efforts at that are not effective, the glycemic goal needs to be raised. During effective treatment of early type 2 diabetes with lifestyle changes or with pharmacological glucose-lowering agents other than a sulfonylurea, a glinide, or insulin, a reasonable glycemic goal might be a normal A1C because such patients are not at risk for hypoglycemia during treatment with currently approved glucose-lowering medications.51Cryer P.E. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA2009Google Scholar That might well be beneficial over a substantial portion of the course of type 2 diabetes. But, such therapies are seldom effective over a lifetime of type 2 diabetes and are not effective in type 1 diabetes. During treatment of type 2 diabetes with a sulfonylurea, a glinide, or insulin, or of type 1 diabetes with insulin, the glycemic goal might be an A1C <7%.53Skyler J.S. Bergenstal R. Bonow R.O. et al.Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials.Diabetes Care. 2009; 32: 187-192Crossref PubMed Scopus (463) Google Scholar, 58American Diabetes AssociationStandards of medical care in diabetes.Diabetes Care. 2011; 34: S11-S61Crossref PubMed Scopus (2613) Google Scholar That sometimes can be accomplished safely with a sulfonylurea or even with insulin shortly after oral agent failure in type 2 diabetes,59UK Hypoglycaemia Study GroupRisk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.Diabetologia. 2007; 50: 1140-1147Crossref PubMed Scopus (777) Google Scholar and with insulin very shortly after the diagnosis of type 1 diabetes (ie, in the “honeymoon” period). If such an A1C is not achievable safely, there is demonstrable benefit from reducing the A1C level from high to lower, albeit still above optimal, levels.60Lachin J.M. Genuth S. Nathan D.M. Zinman B. Rutledge B.N. Effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trial—revisited.Diabetes. 2008; 57: 995-1001Crossref PubMed Scopus (415) Google Scholar Indeed, a mean A1C of 7.5% was associated with an all-cause mortality risk ratio of 1.0 in the UK General Practice Research Database.30Currie C.J. Peters J.R. Tynan A. et al.Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.Lancet. 2010; 375: 481-489Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar Finally, glucose levels low enough to prevent symptoms of hyperglycemia become an appropriate goal in individuals with a limited life expectancy or functional capacity in whom glycemic control is unlikely to be beneficial. Glycemic control is, of course, only one aspect of the management of diabetes. Interventions aimed at multiple risk factors—advice concerning diet, exercise, and smoking cessation, blood pressure control and blood lipid control, along with glycemic control—produce both microvascular and macrovascular benefits.61Gæde P. Vedel P. Larsen N. Jensen G.V.H. Parving H.-H. Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med. 2003; 348: 383-393Crossref PubMed Scopus (3904) Google Scholar